One step synthesis for alkyl 2-fluoroacrylates

This application is a 35 U.S.C. § 371 application of PCT/US2020/060112, filed on Nov. 12, 2020 which claims the benefit of U.S. Provisional Patent Application Ser. No. 62/935,218, filed on Nov. 14, 2019. The entire contents of the above applications are hereby incorporated by reference.

The present invention relates to a one step process for the synthesis of alkyl 2-haloacrylates. The process does not require isolation of an intermediate and provides an improved yield compared to methods used in the art.

Alkyl 2-haloacrylates (particularly alkyl 2-fluoroacrylates) can be used as monomers for preparing a variety of polymers. These poly (alkyl 2-haloacrylates) can be used as films, in plastics, and as medicaments.

The literature discloses various processes for preparing alkyl 2-haloacrylates. However, these processes suffer from a number of drawbacks, including low product yield and/or the need to isolate intermediates as well as the use of highly toxic reagents.

A process for the preparation of methyl α-fluoroacrylate comprising admixing dimethyl oxalate with methyl fluoroacetate in the presence of sodium methoxide is described in U.S. Pat. No. 3,262,968 (Example 1). The reported conversion of methyl fluoroacetate was 89%. However, the process used an excess of solvents (greater than 170 parts tetrahydrofuran and 650 parts methylene chloride) and the product mixture contained significant residual methyl fluoroacetate (classified as “extremely hazardous” by the World Health Organization).

A process for preparing 2-fluoroacrylic esters involving the hydrolysis of hydroxymethyl-fluoromalonic esters followed by decarboxylation and re-esterification is described in Gassen et al., J. Fluorine Chemistry, 55, (1991) 149-162. A process for the synthesis of fluoroacrylic acid esters (e.g., methyl α-fluoroacrylate), involving hydroxymethylation of dialkyl malonate with formaldehyde, isolation of an intermediate, acid hydrolysis and further purification is described in CA1280118C. The reported yield was 58%. A process for preparing 2-haloacrylic esters involving the hydroxylmethylation of dialkyl malonate with formaldehyde, isolation of an intermediate, followed by nucleophilic halogenation and decarboxylation is described in WO 2015/193392. The reported yield was less than 70%. The additional processing steps and low yields make these processes undesirable for many applications.

The present description provides a process for the synthesis of alkyl 2-haloacrylates that occurs in the same vessel and/or reaction mixture, does not require the isolation of an intermediate, does not require the use of extremely toxic reagents, reduces synthetic steps, and provides an improved yield compared to methods used in the art.

Disclosed herein is a process for preparing a haloacrylate compound comprising contacting a malonate compound corresponding to the structure of Formula 1

with an aldehyde to form a reaction mixture, wherein each Rgroup is independently alkyl or aryl and X is fluoro, chloro, bromo, or iodo; and heating the reaction mixture in the presence of a base to form a haloacrylate compound corresponding to the structure of Formula 2

wherein Ris hydrogen, alkyl, or aryl, and the overall yield of the compound corresponding to the structure of Formula 2 is at least 75% based on the amount of the compound corresponding to the structure of Formula 1.

Also disclosed herein is a process for preparing a haloacrylate compound comprising contacting a compound corresponding to the structure of Formula 1

with an aldehyde to form a reaction mixture, wherein each Rgroup is independently alkyl or aryl and X is fluoro, chloro, bromo, or iodo; and heating the reaction mixture in the presence of a base to form a haloacrylate compound corresponding to the structure of Formula 2

wherein Ris hydrogen, alkyl, or aryl, and conversion of the compound corresponding to the structure of Formula 1 to the compound corresponding to the structure of Formula 2 occurs in the same reaction mixture.

Also, disclosed herein is a process for preparing a fluoroacrylate compound comprising contacting a compound corresponding to the structure of Formula 3

with a formaldehyde, preferably paraformaldehyde or formalin, to form a reaction mixture, wherein each Rgroup is independently alkyl or aryl; and heating the reaction mixture in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 4

wherein the overall yield of the compound corresponding to the structure of Formula 4 is at least 75% based on the amount of the compound corresponding to the structure of Formula 3.

Also disclosed herein is a process for preparing a fluoroacrylate compound comprising contacting a compound corresponding to the structure of Formula 3

with a formaldehyde, preferably paraformaldehyde or formalin, to form a reaction mixture, wherein each Rgroup is independently alkyl or aryl; and heating the reaction mixture in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 4

wherein conversion of the compound corresponding to the structure of Formula 3 to the compound corresponding to the structure of Formula 4 occurs in the same reaction mixture.

Additionally, the disclosure is directed to a process for preparing patiromer calcium sorbitex comprising preparing the fluoroacrylate of Formula 2A by the process described herein; forming a polymerization reaction mixture comprising divinyl benzene, 1,7-octadiene, and the fluoroacrylate of Formula 2A to form crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; deprotecting the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt to form crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer and contacting with sorbitol to form patiromer calcium sorbitex (i.e., sorbitol-loaded crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer).

Other objects and features will be in part apparent and in part pointed out hereinafter.

A process is described herein for the preparation of alkyl or aryl haloacrylates in which a dialkyl or diaryl halomalonate is contacted with an aldehyde, preferably, formalin or paraformaldehyde, to form a reaction mixture which is heated, typically in the presence of a base, to form the alkyl or aryl haloacrylate.

For the process described herein, the conversion of a compound corresponding to the structure of Formula 1 to a compound corresponding to the structure of Formula 2, or a compound corresponding to the structure of Formula 3 to a compound corresponding to the structure of Formula 4, occurs in the same reaction mixture. The process does not require isolation of an intermediate. Thus, for a batch process, the conversion of a compound corresponding to the structure of Formula 1 to a compound corresponding to the structure of Formula 2, or the conversion of a compound corresponding to the structure of Formula 3 to a compound corresponding to the structure of Formula 4, occurs in the same reaction mixture, typically in the same vessel. For a continuous process, the conversion of a compound corresponding to the structure of Formula 1 to a compound corresponding to the structure of Formula 2, or a compound corresponding to the structure of Formula 3 to a compound corresponding to the structure of Formula 4, occurs in the same reaction mixture.

The process described herein are more efficient than methods described in the prior art in terms of use of reagents and manufacturing steps because the synthesis can occur in one reaction vessel without transfer or isolation of an intermediate. Further, the product yield is improved over methods described in the prior art for preparing the alkyl 2-haloacrylates.

The production of methyl 2-fluoroacrylate (MFA) from dimethyl fluoromalonate (DMFM) can be accomplished in high yields in a simplified one-pot batch process. A formaldehyde source (e.g., paraformaldehyde and formalin) can be used as reactants with an excess of 10 mol % being sufficient.

A solvent is typically used for this process. Usually, a polar aprotic solvent is used, and typically a high boiling point, polar aprotic solvent. Typical solvents include dimethyl sulfoxide, N-methyl pyrrolidone, and sulfolane; more typically, the solvent is sulfolane.

The concentration of DMFM can be in the range of 10 to 60 wt. %, 20 to 50 wt. %, 30 to 40 wt. %. Typically, the concentration of DMFM is in the range of 35 to 40 wt. %; more typically, the concentration of DMFM is about 37 wt. %.

A base is typically used as a catalyst in this process. Organic bases, such as triethylamine, pyridine, pyrrolidine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and (1,4-diazabicyclo[2.2.2]octane, are capable of promoting the reaction. Inorganic bases, such as aluminum oxide, calcium oxide, and potassium carbonate, are also capable of promoting the reaction. Typically, potassium and cesium carbonate were used, with cesium carbonate producing higher yields.

The process starting temperature can range from 10 to 120° C. Dosing the aldehyde reagent to the reaction mixture produces a rapid exotherm. This exotherm is considered to be the condensation reaction leading to an intermediate. Accordingly, the temperature for dosing formaldehyde is controlled below 30° C. After the exotherm, the temperature of the reaction mixture is typically increased and reaction proceeds to form the desired product. This is considered to be a decarboxylation reaction.

The temperature for the reactive distillation (e.g., a decarboxylation and distillation) can range from 60 to 150° C., 70 to 140° C., 80 to 135° C., 90 to 130° C., or 100 to 140° C.; preferably, a temperature of about 110 to 130° C. is used, or about 120° C. Lower temperatures can be used, but may slow down the reaction and produce MFA at low yields.

Pressure for reactive distillation can range from 50 to 1000 mbar, 70 to 750 mbar, 90 to 500 mbar, or 100 to 300 mbar; typically, the pressure is about 200 mbar. At lower pressures, more distillate may be collected at a faster rate; however, more solvent may also be collected.

Overall yields can be 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 97% or greater, in relation to amounts of a compound corresponding to the structure of Formula 1 (or a compound corresponding to the structure of Formula 3). Overall yields may be up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 97%, in relation to the amounts of a compound corresponding to the structure of Formula 1 (or a compound corresponding to the structure of Formula 3). Overall yields can range from 75 to 97%, 80 to 95%, 85 to 97%, or 85 to 90%, in relation to the amounts of a compound corresponding to the structure of Formula 1 (or a compound corresponding to the structure of Formula 3). As described herein, crude (unpurified) yields up to 92.7% were achieved, in relation to amounts of a compound corresponding to the structure of Formula 1 (or a compound corresponding to the structure of Formula 3).

Additionally, disclosed herein is a process for preparing a haloacrylate compound comprising contacting a compound corresponding to the structure of Formula 1 with an aldehyde, preferably paraformaldehyde or formalin, to form a reaction mixture comprising the aldehyde and a compound corresponding to the structure of Formula 1

wherein each Rgroup is independently alkyl and X is fluoro, chloro, bromo, or iodo; and heating the reaction mixture in the presence of a base to form a haloacrylate compound corresponding to the structure of Formula 2

wherein Ris hydrogen, alkyl, or aryl, and either (i) the overall yield of the compound corresponding to the structure of Formula 2 is at least 75% based on the amount of the compound corresponding to the structure of Formula 1 or (ii) conversion of the compound corresponding to the structure of Formula 1 to the compound corresponding to the structure of Formula 2 occurs in the same reaction mixture.

Usually in the process described herein with respect to compounds of Formulae 1 and 2, the aldehyde is paraformaldehyde or formalin and Ris hydrogen.

More typically, in the process described herein with respect to compounds of Formulae 1 and 2, the aldehyde is paraformaldehyde or formalin, Ris hydrogen, and X is fluorine.

Disclosed herein is a process for preparing a fluoroacrylate compound comprising contacting a compound corresponding to the structure of Formula 1A with paraformaldehyde or formalin to form a reaction mixture of paraformaldehyde or formalin and a compound corresponding to the structure of Formula 1A

wherein each Rgroup is independently alkyl or aryl; and heating the reaction mixture in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 2A

wherein the overall yield of the compound corresponding to the structure of Formula 2A is at least 75% based on the amount of the compound corresponding to the structure of Formula 1A.

Also disclosed herein is a process for preparing a fluoroacrylate compound comprising contacting a compound corresponding to the structure of Formula 1A with paraformaldehyde or formalin to form a reaction mixture of the aldehyde and a compound corresponding to the structure of Formula 1A

wherein each Rgroup is independently alkyl; and heating the reaction mixture in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 2A

wherein conversion of the compound corresponding to the structure of Formula 1A to the compound corresponding to the structure of Formula 2A occurs in the same reaction mixture.

Usually in the process for preparing the haloacrylate of Formula 2 or the fluoroacrylate of Formula 2A, the reaction mixture comprises paraformaldehyde or formalin.

Typically in the process described herein for preparing a compound corresponding to the structure of Formula 2 or 2A, the overall yield of the compound is at least 75%, 80%, 85%, or 90% based on the amount (number of moles or equivalents) of the compound corresponding to the structure of Formula 1 or 1A.

In the process described herein for preparing a compound corresponding to the structure of Formulae 1, 1A, 2, and 2A, Rcan be C-Calkyl. Typically, Ris methyl, ethyl, or propyl, and more typically, Ris methyl.

The base used in the process can comprise an organic nitrogen base, an alkaline earth metal hydroxide, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkali metal carbonate, an alkaline earth metal hydrogen carbonate, an alkali metal hydrogen carbonate, or a combination thereof.

The base can comprise aluminum oxide, calcium oxide, barium oxide, triethylamine, pyridine, pyrrolidine, morpholine, lutidine, collidine, picoline, trimethylamine, tripropylamine, tributylamine, dimethylethylamine, dimethylpropylamine, dimethylbutylamine, diethylmethylamine, diethylpropylamine, diethylbutylamine, N,N-diisopropylmethylamine, N,N-diisopropylethylamine, N-ethyldiisopropylamine, N,N-dimethylethylamine, N,N-diethylbutylamine, 1,2-dimethylpropylamine, N,N-diethylmethylamine, N,N-dimethylisopropylamine, 1,3-dimethylbutylamine, 3,3-dimethylbutylamine, N,N-dimethylbutylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, lithium hydroxide, sodium hydroxide, potassium hydroxiderubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, rubidium hydrogen carbonate, cesium hydrogen carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, strontium hydrogen carbonate, barium hydrogen carbonate, or a combination thereof; preferably, the base comprises lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or a combination thereof; more preferably, the base comprises potassium carbonate, cesium carbonate, or a combination thereof. Typically, the base comprises cesium carbonate.

The reaction mixture can be heated to a temperature of at least about 110° C., from about 110° C. to about 170° C., from about 110° C. to about 160° C., from about 110° C. to about 150° C., from about 110° C. to about 140° C., from about 110° C. to about 130° C., from about 115° C. to about 170° C., from about 115° C. to about 160° C., from about 115° C. to about 150° C., from about 115° C. to about 140° C., from about 115° C. to about 130° C., or from about 115° C. to about 125° C.

The reaction mixture can be heated to reflux.